The maintenance of skeletal muscle mass is controlled by a balance between protein synthesis and protein degradation which the muscle fibers dynamically regulate in order to adapt to differential levels of physical activity. When the balance favors protein synthesis, muscle mass increases, when the balance favors proteolysis, muscle mass decreases and the muscle atrophies. Factors that lead to muscle atrophy include muscle injury, joint immobilization, prolonged bed rest, glucocorticoid treatment, sepsis, cancer, aging and muscle denervation.
ATP-dependent protein degradation, mediated by the ubiquitin proteasome system (UPS), is increased in atrophying muscle through activation of the muscle-specific E3 ubiquitin ligases atrogin (also known as MAFbx, muscle atrophy F box protein) and MuRF1 (muscle-specific ring finger 1) (Bodine et al., 2001a; Gomes et al., 2001; Lecker et al., 2004). Use of a proteasome inhibitor (Beehler et al., 2006) or genetic deletion of each of the E3 ubiquitin ligases, reduces denervation muscle atrophy (Bodine et al., 2001a), indicating that UPS-mediated protein degradation is a major pathway underlying this process.
Muscle innervation is an important regulator of skeletal muscle mass and function. Individuals, who as a consequence of traumatic nerve injury and motor neuron diseases experience a loss of motor innervation, suffer from highly morbid denervation-associated muscle atrophy for which there is currently no effective therapy. Blocking or reversing denervation-associated muscle atrophy would be an important step towards reducing the extent of permanent damage that results from motor neuron injuries.